There is an unmet need for new and safer estrogen therapies (ET) to treat the symptoms associated with low levels or a lack of estrogens, including decreased sexual motivation, hot flushes, sleep disorders, depression/anxiety, brain and spinal cord trauma, amyotrophic lateral sclerosis, and cognitive dysfunction. Currently only estrogens alone or in combination with progestins or androgens are available to treat these conditions, including natural or surgical menopause. However, many women cannot or do not want to take estrogens because of their potential side effects, the most critical of which are the effects of estrogen on the uterus and the breast. However, estrogen insufficiency contributes to post-menopausal decline in sexual desire that can lead to female sexual desire disorder (FSDD). Current hormonal therapies for FSDD use treatment with an estrogen and testosterone, but their effectiveness is limited. Estradiol by itself can reinstate sexual desire if given at dosages that produce midfollicular serum estradiol levels (100-300pg/ml). However, at such dosages there are concerns about the risk of breast or uterine cancer, thus all current FSDD treatments use hypoestrogenic treatment (20pg/ml) in conjunction with testosterone when larger amounts of estradiol would likely increase treatment effectiveness. Here we investigate a novel and potentially safe estrogen therapy using 10b,17b-dihydroxyestra 1,4 dien-3-one (DHED) to reinstate sexual receptivity and sexual motivation in rat and monkey models. DHED is an inactive precursor of estradiol; it does not bind to estradiol receptors and thus produces no estrogenic effects in its native form. However, an enzyme converts DHED to estradiol. Our preliminary evidence suggests that this enzyme is only expressed in the CNS thus potentially making DHED a brain-selective prodrug for 17b-estradiol (E2). DHED, which crosses the blood brain barrier, would be inactive outside of the brain, but would deliver effective amounts of E2 to the brain. We propose to use sexual behavior as a model estrogen-responsive system with which to test DHED's potential therapeutic effects. Induction of lordosis in ovariectomized females rats using a sequential DHED and progesterone treatment will test the central activity of DHED. We will then use an ovariectomized monkey model of female sexual initiation to test DHED's efficacy in increasing sexual desire. Dr. Prokai will synthesize DHED for this project and undertake in vivo studies on conversion of DHED to E2. Dr. Merchenthaler's lab will investigate estradiol induced gene expression in the brain and periphery after acute or chronic DHED treatment and investigate DHED's capacity to active female rat sexual receptivity. Dr. Wallen's lab will undertake studies of female rhesus monkey sexual initiation during DHED treatment. Preliminary data from rodent models of hypoestrogenic conditions show that DHED is a brain-selective bioprecursor produg for E2, and is likely to be a safe and effective treatment of conditions due to the lack of estrogens (ovariectomy) or low levels of estrogens (menopause). If successful these studies will revolutionize the treatment of clinical problems resulting from hypoestrogenic conditions.